This project seeks to further define profiles of behavioral changes specifically related to the serotonergic, noradrenergic, and cholinergic inputs to the dentate gyrus of the dorsal hippocampus of rats. The transmitter systems will be manipulated by direct microinfusions of agonists and/or antagonists into the dentate gyrus of feely moving rats concurrently with testing in a Behavioral Pattern Monitor (BPM), which provides detailed measures of the frequencies, durations, and sequential patterns of locomotor and investigatory behaviors. Behavioral profiles related to the activation of alpha versus beta adrenergic and serotonin-1 versus serotonin-2 receptors will be characterized. In vivo functional assessments of interactions among the major transmitters in the dentate gyrus will also be studied. Included in these studies will be noradrenergic, serotonergic, cholinergic, and gabaergic manipulations. Neurotoxin-induced depletions of serotonin or norepinephrine will be used to induce supersensitivity of the respective post-synaptic receptors within the dentate gyrus to determine the ability of the microinfusion technique to detect changes in receptor sensitivity and to assess the relevance of the endogenous inputs to the effects produced by the microinfused agonists. Agonists will be administered at three and 14 days after the introduction of lesions in order to distinguish between pre- and post-synaptic mechanisms of supersensitivity. Experiments are also proposed to assess the functional relevance of the changes in beta-adrenergic and serotonin-2 ligand-binding induced by chronic but not acute treatments with antidepressant drugs, including imipramine, desmethy-limpramine, trazadone, and mianserin. The precise distribution of microinfused serotonin will be assessed by microspectrofluorimetric measures of formaldehyde-induced fluorescence. The extent and specificity of neurotoxin-induced lesions will be determined by liquid chromatography with electrochemical detection. This work is intended to further our basic understanding of the behavioral functions of the major neurotransmitters within the hippocampus and to provide a procedure to assess the functional relevance of changes in transmitter-related ligand-binding measures in neuroanatomically specific manner.